Osteopenia occurs commonly in patients with type I and type II diabetes mellitus. Although the mechanism by which diabetes produces bone loss is unknown, studies in type I diabetec animals suggest that abnormal vitamin D metabolism may play a role. Specifically, studies in streptozotocin-diabetic rats indicate that hypoinsulinemia leads to impaired responsiveness of renal 25(OH)D-1-hydroxylase, low circulating levels of calcitriol and subsequent intestinal calcium malabsorption. Long term malabsorption of calcium may eventually lead to a state of low bone turnover and decreased bone density. Our purpose is to investigate the mechanisms by which the type II diabetic state causes bone loss. Preliminary studies have demonstrated an osteopenic bone lesion and disordered metabolism of vitamin D in two murine models of type II diabetes, the db/db and the ob/ob mouse. In contrast to type I models, these animals exhibit elevated production of 1,25(OH)2D3 in the basal or stressed state. My specific aims are: (1) to further characterize the defect in 25(OH)D-1 and 24R-hydroxylase activity in ob/ob and db/db mice, (2) to explore the etiology of the defective vitamin D metabolism in these mice and (3) to examine the association between altered vitamin D metabolism and murine bone structure. Approximately 8 million people suffer from type II diabetes in the United States. A majority of these patients will develop cortical osteopenia and may be subject to high rates of foot and ankle fracture as a result. Further investigations into the mechanisms by which type II diabetes causes bone loss may result in effective therapy to prevent these complications. Specific methodologies which I will employ in characterizing calcium regulation in diabetic mice include: (1) measurement of intestinal calcium absorption in vivo, (2) measurement of biologically active parathyroid hormone by a cytochemical assay, (3) determination of in vitro 25(OH)D-1 and 24R-hydroxylase activity in homogenated kidney preparations, (4) evaluation of 25(OH)D-1 and 24R-hydroxylase activity in kidney tubule tissue culture and (5) calculation of bone histomorphometric indices from sections of mouse femur.